What should you know

Daily Press Librarian Tracy Sorensen and Reporter Bob Evans amassed hundreds of documents and records about the anthrax vaccine to help answer your questions about the safety and effectiveness of the drug.

At best, it means that a very small percentage of people will have serious side effects resulting from the vaccine.

Every vaccine causes adverse reactions in some percentage of the population, either because of the vaccine itself, the additives and preservatives used to make and deliver it - or the act of getting a vaccine - says Gene Stollerman, professor emeritus of medicine and public health at Boston University.

Stollerman was chairman of a government panel in the 1970s that passed judgment on the safety and worth of many vaccines used today, including the anthrax vaccine. He's been an internationally known expert on vaccines and public health for more than 40 years.

Pentagon records show that doctors involved in enacting the anthrax vaccine program met in 1999 and expected 0.2 percent of those who received the vaccine to have "serious adverse reactions." For every 1 million troops inoculated, that would result in 2,000 serious illnesses. Pentagon officials now say that if there's a rate of reaction, it's so small, they can't measure it.

The idea of no one getting sick after a vaccination isn't realistic, Stollerman says. Studies have found that people get symptoms of illness even when given a placebo (a shot containing no drugs), apparently from the anxiety of getting a shot. Some published studies have found as many as 50 people getting hives after receiving injections of water alone, he says.

In addition to this suggestive reaction, some percentage of the population is bound to be allergic or otherwise physiologically reactive to the contents of a vaccine, he says. Genetics can play a big part in this.

The key is to monitor vaccines and use them only when the risk of not vaccinating people is greater than the most serious reactions. "We had to give the Sabin (polio) vaccine, knowing that perhaps one in many million might contract polio" from taking it, Stollerman says. But that meant all but one in those millions wouldn't get the crippling disease, so the risk-benefit ratio was positive.

When doctors talk about the safety of the vaccine, they balance the risk against the reward. "The public doesn't do that," Stollerman says. It mistakenly thinks that "safe" means no one gets sick or hurt.

Will the vaccine protect me from inhaled anthrax?

The Pentagon and the Food and Drug Administration say yes. A federal judge ruled last year that the two agencies had no legal basis for making that statement, because the licensing rules for establishing the effectiveness of the vaccine hadn't been followed. As a result, the military had to begin asking troops for permission before inoculating them.

The Pentagon and critics of the vaccine agree on very little, but there's no doubt that inhaled anthrax is the real threat to troops or from terrorists.

Many scientists say no one can say for sure whether the drug is effective against inhaled anthrax, in part because it would be unethical to test the question by exposing human beings to anthrax. A 1962 study that provided the data for the vaccine's license is the only test of what happens when humans who've received the drug come in contact with anthrax.

The same study found that some people exposed to inhaled anthrax suffered no ill effects. Several government scientific panels cited numerous flaws in that study. They said there was insufficient evidence of protection against inhaled anthrax to license the drug for that purpose, in part because there were so few examples of it to be sure. But they agreed to license the product for protection against anthrax on the skin, which is also deadly but is easily treated by antibiotics after exposure. Even then, the 1962 study found, the vaccine prevented only 92 percent of the cases involving skin contact.

After the anthrax vaccine came under attack from scientists, veterans and active-duty military personnel in the late 1990s, the Pentagon and current FDA officials used the same data - and some experiments involving animals - to assert that it worked for inhaled anthrax, too. Animal experiments as substitutes for clinical trials with humans weren't approved by the FDA for vaccines until 2002, however, and many scientists say they're poor predictors of how a vaccine will affect a human.

Jack Melling, a longtime expert on vaccines who ran the British government's biodefense laboratory, told Congress that the human immune system was too complex to be sure that any animal experiments would mimic those on humans. Even then, he said, some percentage of the human population won't be protected, anyway, because of differences in genetics and metabolism.

Ken Alibek, who ran the former Soviet Union's biological warfare program before he defected in 1992, told Congress that "vaccines would be of little use." He said there was little likelihood that the vaccine used by the U.S. military would work against strains of anthrax developed by his scientists and others more than a decade ago. Anyone trying to manufacture anthrax for terrorism or warfare would likely use those methods or strains, he said - probably with the help of some of the 32,000 people who worked in Soviet labs.

Experimental exposure of humans to anthrax spores or spray in the air isn't ethically possible, but there have been accidents involving anthrax at military labs. Bill Patrick is the former head of the product development division of the U.S. biological warfare program. He says two workers at the labs at Fort Detrick, Md., died after accidental exposure to anthrax there. Both had been vaccinated before their exposures. Both were given booster shots and other treatments after their illnesses had been diagnosed, in the hope of conquering the infection.

One was a lab worker who received a huge dose that Patrick says he wouldn't expect the vaccination to defeat. The other was an electrician who "was simply changing light bulbs" and got a very low dose.

"We could never determine why the vaccination wasn't more effective for the electrician," Patrick says. The best guess is that his genetic makeup made him one of the people who had a very low tolerance for anthrax, despite boosting his immune system with the vaccine. Just as differences in genetics make someone likely or unlikely to have an adverse response to the vaccine, biology makes some people more susceptible to the anthrax spores that carry the disease, he says. "That's just the way nature works."

He says the science of determining how many people fit into the more susceptible category - and who they are - isn't very advanced. "No vaccine is going to protect everybody," he says. "But what you're trying to do is protect the majority of your citizens, your soldiers."

Whether there's sufficient evidence to label the vaccine effective against inhaled anthrax is the central issue in the lawsuit brought by military members against the Pentagon's vaccination program. A federal district judge ruled that there was insufficient evidence the license was properly granted for protection against inhaled anthrax. The judge made the ruling after a former head of the FDA's licensing department testified that the vaccine hadn't been legally approved. That ruling is being appealed, and that's the reason the military now can offer the vaccine only on a voluntary basis.

I hear about autoimmune disorders. What are they, and why are they related to the shot?

Autoimmune disorders cover a broad spectrum of reactions in which the body's normal defense system against infection or disease goes haywire and starts attacking healthy tissue or cells.

Vaccines work by entering the body and causing it to form responses, but in a certain percentage of people, the body overreacts. That reaction can either be as an allergic reaction, which normally is short-term but can be serious (anaphylaxis, for instance, which can be a life-threatening breathing problem), or an autoimmune reaction, which involves a more serious problem.

Statistical analyses of people who report problems after vaccinations show that a higher percentage have symptoms consistent with autoimmune problems after the anthrax shot, compared with other vaccines. Other researchers have found in experiments with animals that even small doses of anthrax vaccine can trigger autoimmune reactions that cause diabetes.

Pentagon officials downplay those studies as irrelevant for humans because of the biological differences between the animals in the studies and humans. Critics note that some of the same animals used in the diabetes studies were used by the military in statements that the vaccine is effective against inhaled anthrax. The military's health data system from 1998 to 2000 reported that troops inoculated for anthrax were diagnosed three to four times more often for diabetes mellitus after receiving the anthrax vaccine than before they got the shot. Pentagon officials say that when those troops are compared with the entire military, there's no excess incidence of diabetes, however, which should mean that the vaccine isn't a likely cause of the disease.

In 2003, the federal Centers for Disease Control and Prevention identified six studies that should be undertaken to further explore possible problems with the vaccine. The problems were identified from the military's hospitalization and other data. Four involve autoimmune problems, said Michael M. McNeil, the agency's team leader for anthrax vaccine safety. They are:

Optic neuritis. This disease involves the body attacking the optic nerve. Several patients who received the vaccine have been diagnosed.

Arthritis.

Systemic lupus. A rare disease usually contracted by women.

Stevens-Johnson syndrome. A painful, rare skin disorder that can destroy mucous membranes, the eyes and other parts of the body.

Many scientists think that these reactions are highly influenced by genetics, but so far, there's no reliable test to predict how most people will respond to any given vaccine. There are some genetic tests given in the military that are used for screening vaccines, but this is an emerging area.

How many people have died from the anthrax shot?

The Pentagon doesn't acknowledge any deaths caused by the vaccine. According to data from the FDA and CDC, at least 21 people have died after receiving the anthrax vaccine. This data signifies only that the deaths took place after the shots were given - not necessarily that there's a cause and effect.

The military also hasn't reported all the information that it has on post-vaccination medical problems, so the number could be larger. The Daily Press found two other deaths that followed the vaccination that hadn't been reported before it talked to the widows of servicemen who received the shot.

How many people get seriously ill from the anthrax shot?

That's hard to answer, and even then, it depends on whom you ask.

The military's official answer is that fewer than two-tenths of 1 percent have been found by medical experts to suffer serious adverse events attributable to the anthrax shot.

More common are minor reactions such as skin irritation, a sore arm, redness near the injection point or fatigue that lasted a few days or weeks. Up to a quarter of those who get the shot will feel weak for a few days to a few weeks, a recent Pentagon summary says. A third will complain of muscle pain, and up to 15 percent will have pain in their joints for up to a month, the summary says.

About 30 percent of men and 60 percent of women are likely to experience irritation or a small rash near the injection point for a few days, and half will feel a small bump there for a few weeks. Up to 35 percent of those who get the shot will have joint or muscle aches, flulike symptoms, nausea or headaches that last up to a week, though sometimes longer.

All these figures are the results of teams of medical experts evaluating data submitted to the federal government's Vaccine Adverse Event Reporting System, known as VAERS. It's managed by the CDC and the FDA. This computerized system is used for all vaccines licensed in the United States, and it's the primary way that medical experts and the government monitor the safety of vaccines once they're licensed.

Doctors, patients and family members can file these reports by telephone, online or mail. Medical experts take information from each incident to determine whether there's a relationship or not. Most aren't related, at least according to the experts who review the reports.

There are severe limits with this system.

Not all reports are bona fide reactions to the vaccine. Some are just illnesses that come after receipt of a vaccine. Reports are supposed to be filed for any reaction after a vaccination, not just those where someone thinks that there's proof of a cause and effect.

This is what scientists call a "passive" monitoring system: It relies on people to be motivated to report something and to recognize a need to report it. Many studies have found that this method of gathering data isn't very accurate and typically undercounts the number of reactions related to a vaccine - by as much as 100 percent.

A study involving postal workers and others who received anthrax vaccinations after the 2001 letters mailed with anthrax spores used what's called an "active" follow-up system. That's where health researchers actively contact and interview people who got the shots to determine whether there are adverse reactions. That study found 12 confirmed "serious adverse events" after the vaccinations, but only two of them were reported through the VAERS system. Ultimately, none was deemed to be the result of the anthrax vaccination.

"Active" follow-up research is more likely to find a problem. But it can be very expensive and difficult to do correctly. Nearly always, there are limits on how reliable they can be. That's usually because there are either a small number of people involved to start (which makes it easier to afford and easier to avoid problems in data collection) - or because following the health of a large number of people makes it difficult to figure whether an illness is related to the vaccine or some other cause.

For instance, a recent review of cases by doctors at Walter Reed Army Medical Center in Washington found that of 260 patients who received the shots in 1998 and 1999, six - 2.3 percent - required medical treatment for acute problems. That's a much higher percentage than the VAERS data covering all the shots given for a longer period, but it reflected a more active monitoring of illnesses.

At a congressional hearing in October 2000, 10 men and women who thought that they suffered poor health because of the vaccine - or had lost a loved one because of the vaccine - testified. The Pentagon says the anthrax vaccine was related to the poor health of only one of them: an airman who developed a rare nervous disorder that caused him to pass out and fall repeatedly.

A Daily Press investigation into military medical records involving troops given the vaccine found that more than 2 million clinic visits that fit the criteria of VAERS weren't reported after anthrax vaccinations from 1998 to 2000. It also found that 20,765 hospitalizations that met the VAERS definition of a "serious adverse event" weren't reported during that time.

Doctors and researchers who run the VAERS system say their review process would have been seriously bogged down if all those reports had been filed. But the military had told Congress that hospitalizations and other serious events would be reported to VAERS - one of the few places where the public can look for information on a vaccine.

Can we trust any of those numbers?

Pentagon officials say they've done everything possible to give people the facts, but critics accuse the military of hiding or ignoring vaccine-related illnesses.

For instance, the Defense Department's official position is that the rates of reaction to the anthrax shot are similar to those of other vaccines. But an analysis of all data in the VAERS system for every vaccine licensed in the United States was published last year in a peer-reviewed medical journal. It found that the anthrax vaccine had higher reported reaction rates in every category, compared with other vaccines.

Another data analysis found that though anthrax vaccinations made up less than 1 percent of all vaccinations, anthrax shots accounted for 6.3 percent of all complaints to VAERS in 2003 and 5.2 percent of all reports in 2004.

Those studies occurred after a congressional inquiry found that the military had restricted reports to VAERS from military physicians for several years. Testimony indicated that military doctors had been told not to report reactions to vaccines unless hospitalization - or at least one lost workday - was involved. That didn't count days when someone got "limited duty" because of illness or fatigue for days or even weeks after a shot.

Those instructions were contrary to federal rules for reporting problems in the VAERS system. The rules call for any adverse reaction to be reported, no matter how small or severe - or how unproven the relationship between the vaccine and health problem is.

Military health officials reacted by sending out new orders, requiring reports for any and all reactions. Pentagon data shows that 64 percent of all anthrax vaccinations given to the military since 1998 occurred when reports to VAERS were limited, which would indicate the number of reports was suppressed.

After the change in guidance for reporting cases, the number of adverse reactions reported to VAERS from the anthrax vaccine shot up. That required the manufacturer to list a 100-fold increase in adverse reactions for the vaccine this year, compared with its disclosures in 1999.

The abrupt change is one of the big reasons that critics of the mandatory vaccine program give for questioning the safety - and trustworthiness - of the military's program. They say the military has intentionally kept reports of problems out of public view.

For instance, only 159 reports involving mental health problems after an anthrax vaccination were reported to VAERS during 1998-2001, a four-year period. But Pentagon records for the first three years of that span show that 2,077 people who received the anthrax shot were hospitalized for mental health problems.

And 16,514 more people saw military doctors who diagnosed them with serious mental health problems (diagnoses of "affective psychoses") after vaccination for anthrax. Other variances between the number of cases reported to VAERS and the number documented by the military but not reported to VAERS are contained in the raw statistics of government reports.

Col. John Grabenstein, director of the military's vaccine program, says all this provides a misleading picture of the vaccine's safety. He says the most accurate assessment comes from a study that the military conducted and published in a peer-reviewed scientific journal. It studied the rates of diagnosed illness in all military members who'd been immunized for anthrax from 1998 to the end of 2000. It then compared those rates with the rates of illness for people of the same age, gender, race and other factors in the military who hadn't received the vaccine.

Using standard statistical analysis, the study found that there was no substantial health risk from taking the vaccine during that period. The study was reviewed and approved by panels of civilian scientists. The study was confined to diagnoses at military medical sites.

Even a full count of hospitalizations and clinic visits wouldn't capture all the health problems that followed inoculations for anthrax, says a report by Congress' investigative arm, the Government Accountability Office. The GAO surveyed armed-forces members in the late 1990s. It found that 57 percent of those who had reactions said they didn't report their problems and that half of them feared retribution if they complained.

Troops told the GAO that they didn't file complaints because they thought it would harm their careers. The problem was especially prevalent for pilots, who feared that information about their health status might make them ineligible to fly or maintain commercial pilot licenses.

Other armed-forces members say they've withheld reports of lethargy or other ills that lasted for years. That's because, they say, they've seen others in their units who did complain pushed out of the military with little or no disability compensation.

A study by Grabenstein and others looked at whether those who'd received the vaccine were disabled at a higher rate than other troops. It found that there was no increase in disability after the vaccine, but it didn't include a long-term analysis. Most of those in the study had been vaccinated for less than two years.

The Pentagon says there are 20 safety studies of the anthrax vaccine, involving more than 500,000 recipients, that prove the vaccine's safety. Isn't that good enough?

It might be. What the Defense Department Web site doesn't say is that most of these studies involve very small numbers of troops for limited periods or that the studies have severe limits on their findings for other reasons. Many of these reports also base their findings on the other studies in the list, so you don't really have 18 separate groups of experts coming to independent conclusions.

Many of these reports point out that their conclusions are limited. But the limits aren't often included in the Pentagon's publicity. Nearly all say more research is needed to reach a definitive conclusion about safety or effectiveness against inhaled anthrax spores. They say what's particularly needed is a long-term look at how troops who got the shots fared after five years or more, compared with troops and people who didn't get the shots.

In one prominent case, a report says it shouldn't be taken as a conclusive answer to the safety and effectiveness questions at all - just as a tool for forming hypotheses to get those answers.

What hasn't happened yet is a true, active epidemiological study of the vaccine's use, covering a large number of people for more than three to five years. The CDC, the Institute of Medicine and other groups that have studied the issue - and given the vaccine a limited seal of approval - have all called for this type of study.

The CDC plans to do one, but it hasn't finished designing it and doesn't know when it might be completed, says Michael M. McNeil, the agency's team leader for anthrax vaccine safety.

Cmdr. Margaret Ryan, a doctor and researcher at the Naval Health Research Center in San Diego, says her staff might have an early look at long-term effects of the vaccine ready by the end of 2006. She says the work is part of the Millennium Cohort Study, a huge research project that involves a 21-year look at the health of people in uniform, extending long past their time in service.

If a look at the effect of the anthrax vaccine is ready next year, it would tell only whether there's a measurable difference in the quality of the health of those surveyed in the study, she says. Studies that look at chronic illnesses would take more time.

So tell me about some of those safety studies. What are their strengths, and what are their limits?

Institute of Medicine Committee to Assess the Safety and Efficacy of the Anthrax Vaccine. The Anthrax Vaccine: Is it Safe? Does it Work? (http:nap.edu/catalog/10310.html)

The Pentagon and others point to this report frequently. Critics say it was tainted by post-Sept. 11, 2001, patriotism; undue influence by the military; and limits on the work the panel of scientists that wrote it was asked to perform.

The panel of well-known medical and scientific experts worked under the auspices of the Institute of Medicine, a division of the National Academy of Sciences. The academy is an organization routinely used by Congress and other government agencies to investigate topics that are important to the public. The institute and academy are generally viewed as free from political influence, but critics of this study say that standard might not hold true for this report.

Brian Strom was chairman of the group that published the 2002 report. He said that if anything, his panel began with a prejudice against the vaccine and the military - in part because scientists tend to be skeptical and because the vaccine was so old, originating in the 1950s.

But after having full access to the military's data and testing its hypotheses, the group decided that the vaccine was reasonably safe - but should be upgraded and made with modern processes that might prove less prone to causing reactions, Strom said.

The committee said the vaccine was probably effective against inhaled anthrax, primarily because of tests on animals.

What the Pentagon's information on the vaccine doesn't say (unless you read the entire 288-page report) is that the institute's panel says there was "limited" data on long-term health issues related to the vaccine. It called on the Defense Department to develop a system to more effectively monitor the long-term health of vaccine recipients in a way that didn't depend solely on military hospitals or voluntary reporting of medical problems.

One member of the panel, epidemiologist Linda D. Cowan, says the long-term study being contemplated will probably be done well after the next version of the vaccine is put to use.

In the absence of such a study, the committee says, it had to base much of its conclusions on the data entered into VAERS and on a military health tracking system that had only three years of data. The committee found "no convincing evidence" of problems based on that data and in several studies that it examined involving small groups. But it also noted that it wasn't asked to undertake an analysis of cause-and-effect relationships between the vaccine and illnesses that followed receipt of the shot.

At the time, congressional studies found that VAERS data on adverse events was artificially low. That's because, they found, military doctors had been instructed to report only the most serious incidents - and because many military personnel were discouraged from complaining about side effects.

Critics of the 2002 institute committee's work point out that a separate panel of scientists just as distinguished and respected had concluded - two years earlier - that there simply wasn't enough good evidence to say whether the anthrax vaccination used by the military was safe or effective.

There were very few additional scientific studies completed and published between the two institute reports. The big difference was that the second panel accepted a number of unpublished studies done by the military or government employees, while rejecting nearly all unpublished studies by those critical of the vaccine's health effects.

The second study was also sped up, by about 18 months, after letters containing anthrax were sent to members of Congress and the public. A number of scientists have suggested that the 2002 report's conclusions were overly influenced by the atmosphere of national support for the military and its programs in the aftermath of those attacks - which took place shortly after the Sept. 11, 2001, terrorist attacks. Members of the 2002 panel deny this. Strom and others say this didn't adversely influence their work.

The Defense Department Web site on the anthrax vaccine and its literature doesn't refer to the 2000 study at all.

The Pentagon and FDA cite this as a significant report supporting the safety of the vaccine. But the report itself says that though it found "no evidence of a significant safety problem," the data it had to work with was so limited - and potentially misleading - that no "definitive conclusions" should be drawn.

"Consequently, the relationships described in this report have value primarily for hypothesis generation," not a thumbs-up or thumbs-down on safety, the report says.

It involves analyses of reports to VAERS by seven doctors and scientists known as the Anthrax Vaccine Expert Committee. The Department of Health and Human Services picked the panel - at the request of the Pentagon - so that it would be objective, John Sever says. He's a longtime researcher in vaccines who works at the Children's National Medical Center in Washington and was chairman of the panel.

The Pentagon took this step after dozens of veterans complained publicly about debilitating health problems following anthrax vaccinations and after Congress questioned the Pentagon's ability to manage the evidence.

Doctors and patients file VAERS reports with the FDA and the CDC. VAERS includes every vaccine licensed in the United States. These reports are simply reports and don't document a cause and effect between a vaccination and a subsequent health problem. The "events" simply follow receipt of a shot in time.

Medical experts must analyze the data to see whether there's a further connection. Events are divided into "local" (such as a red spot, bump on the arm or soreness near the site of the shot) or "systemic," involving a system of the body, such as the vascular (veins and arteries), pulmonary (lungs and breathing) or cardiovascular (heart).

In the second and final version of its report, published in 2004, the committee looked at 1,841 reports -involving 3,991 events - from 1998 to 2001. Most reports involved military members - more than 500,000 people who'd received about 2 million doses of the vaccine during the study period.

The panel says that based on this data, the anthrax vaccine wasn't more likely to cause adverse events than other vaccines. It found only 147 serious or otherwise medically important reports of reactions. But after analysis, it decided that only 26 of them were probably or certainly the result of the vaccine.

In addition, it found 20 events that couldn't be classified as related or not - including two deaths. Sever says that means there wasn't enough evidence one way or the other to make a determination. He notes that there were many limits on the data available to the panel. It could ask for more information from the government contractor that runs VAERS, but "more often than not, the desired information cannot be obtained," the panel's report says.

It says women, members of the Air Force and older people (ages 30 and up) were more likely to report reactions than men, members of the other services or people younger than 30.

Women were more likely to report minor, local soreness and reactions. But men were more likely to report fatigue and joint pain - which surprised the scientists because women are normally more likely to have joint pain than men under normal circumstances.

Sever says his panel considered whether the joint pain identified in the VAERS reports might be representative of long-term autoimmune problems or temporary reactions. He says the panel found that most of those in the VAERS database suffered these pains for less than three months, which would indicate that it reflected a hypersensitivity to the vaccine, not the onset of autoimmune disease.

The CDC has a more thorough evaluation of this issue under way, one of six studies that look in depth at possible problems resulting from the anthrax vaccine, said Michael M. McNeil, the agency's team leader for anthrax safety. He said he didn't know when the study would be done.

The validity of VAERS data to help establish the safety of a vaccine depends greatly on how effectively doctors and patients report the adverse events that follow vaccinations. Studies have found that only a small part of even legitimate problems are reported.

A study for the CDC, for instance, found that of 71 potentially serious adverse events reported by the civilians who took the vaccine after the 2001 anthrax-letter scares, only five came from VAERS reports. Other studies of VAERS data found that only about 1 percent of adverse reactions are ever reported, no matter which vaccine is involved.

The Daily Press found that during 1998-2000, a Defense Department database counted 20,765 hospitalizations of troops after they'd received anthrax vaccinations. However, like VAERS, this was a temporal relationship - not necessarily cause and effect. A panel of civilian researchers reviewed that data and said it was unlikely that the vaccine caused significant health problems.

David Geier has written and published more than 40 articles involving VAERS data in peer-reviewed science and medicine journals. He says panels such as the expert committee have inherent bias because of the subjectivity of analyzing events and trying to decide which ones are related to the vaccine and which are not. When scientists are trying to figure out whether there's an unknown phenomenon resulting from vaccinations, they shouldn't be letting that kind of personal bias come into play, he and others say.

Geier and his father - Mark Geier, who's been involved in vaccine research and development for more than 30 years and was on the staff at the National Institutes of Health in the 1970s - did a statistical analysis of VAERS data on anthrax. They then compared it with other vaccines.

They focused on complaints about gastrointestinal problems and joint pain because both are thought to be indicators of autoimmune reactions, which can have severe long-term health effects. Troops afflicted with the illnesses typical of Persian Gulf War veterans have frequently been diagnosed with symptoms of autoimmune disorders, as have many who've complained of health problems after anthrax vaccinations.

The Geiers found that there were higher rates of gastrointestinal reactions after the anthrax vaccine than for any other vaccine normally given to adults.

They also found that anthrax vaccinations were followed by higher rates of complaints about joint pain and soreness than the hepatitis A vaccine or the tetanus/diphtheria vaccine - vaccines they said are about average for reactions among all vaccines. Anthrax had a rate six times that of hepatitis A.

The Geiers caution that their findings should be cause to examine the safety of the vaccine further. They say the findings shouldn't become evidence that the shot isn't "safe" or that it shouldn't be given to protect troops where anthrax might become a weapon.

Workers at Fort Detrick take many vaccines to protect their general health and as a defense against the chemicals and other substances that they work with.

Several studies of those workers, dating to 1958, have been done to determine whether exposure to many vaccines over a lifetime might affect human health. In each study, the researchers found "no known long-term patterns of side effects from the anthrax vaccine," the Defense Department says. But there are also many flaws in these studies, other people say.

For the earliest of these studies, spanning 1956 to 1971, researchers attempted to follow the health of 99 workers. But only 77 were available when 25 years had passed, and only 25 of them had received anthrax vaccinations - making for a very small sample. If those who died or those who declined to provide information are counted, there might be a statistically significant number with problems from the vaccines, skeptics point out.

In the latest version of the studies, published in 2004, researchers picked volunteers from a group of former workers who participated in social events involving former Fort Detrick employees, a type of "alumni" group.

When questioned, former workers "tended to characterize themselves as somewhat less healthy" than a similar group of people who didn't work at Fort Detrick. Reports of "fatigue" - and the prevalence of high levels of monoclonal proteins in the blood of a fifth of the former workers - were the only significant findings, the researchers concluded. (A monoclonal protein is an antibody, or part of an antibody, found in unusually large amounts in the blood or urine of people with multiple myeloma and other types of plasma cell tumors. It's also called an "M protein.")

They said the presence of the proteins was worth further study. They also said it was likely that these workers had a blood condition known as MGUS, which has been linked to multiple myeloma - a rare form of cancer - and other illnesses. The causes of MGUS and multiple myeloma are unknown. About 20 percent to 30 percent of people with MGUS get multiple myeloma, which usually fatal within three few years.

None of the Fort Detrick volunteers for this study had multiple myeloma. But the debilitating nature of the disease makes it unlikely that anyone with multiple myeloma would be participating in the activities from which the study group was drawn - even if they were alive.

That's one of the limits of this study: It started out with some of the happiest - and probably healthiest - former workers from the post and excluded those who might have health problems.

This study, published in 1962, is the basis for the original licensing of the drug. It examined how workers at mills handling animal hides reacted to the vaccine - and whether any who'd been vaccinated were exposed to anthrax and got sick.

The study wasn't seriously questioned until the 1990s. That's when inoculations for anthrax increased from a hundred or so people a year to hundreds of thousands - and when sick service personnel began suing the government and the manufacturer for illnesses they said resulted from the shots. Six unnamed military members filed suit against the government, saying the vaccine had never been properly reviewed and approved for use.

A review of the Brachman study by a panel of scientists assembled by the Department of Health and Human Services in 1975 concluded that despite many limits, the Brachman study established that the vaccine was reasonably safe and effective for protection against skin anthrax infections. The panel said there wasn't enough evidence to say whether the shot was effective against inhaled anthrax, which was the most likely form to be used by terrorists or in wartime.

The Pentagon says this was one of the significant studies supporting the safety of the anthrax shot. But it says the issue of inhaled anthrax was answered by studies involving animals.

Gene Stollerman is professor emeritus of medicine and public health at Boston University and chairman of the panel that reviewed the licensing of the anthrax vaccine for the U.S. Food and Drug Administration in the 1970s. He says that aside from the Brachman study, there was little evidence about the anthrax vaccine available at that time and that "the review of the anthrax was fairly perfunctory" as a result.

The committee faced a choice, he says. If it hadn't labeled the vaccine "safe and effective," it wouldn't have been available at all - except as an experimental drug.

But the data gave no indication of problems, he says, and the military was about the only customer for the vaccine and needed it. At the time, most of those who took the shots worked in military labs. So the shot was approved.

Walter R. Schumm is a professor at Kansas State University who specializes in statistics and scientific methods. He says he found numerous flaws in the math and processes used in the Brachman study. He notes that by the end of the study, more than 75 percent of the workers had dropped out. He also notes that there was nothing reported about their health, which left open how many workers had long-term adverse reactions to the vaccine.

At some mills, workers' health was examined for three months, but at others, he says, it was examined for more than three years.

The circumstances at the mills were also very different: Some mills had high rates of skin anthrax infections, while others had almost no cases. One mill had an epidemic of inhaled anthrax, unlike any of the three other mills. Yet, Schumm says, when the conclusions were drawn, they were lumped together - as if these differences in time and circumstances didn't exist.

Schumm is a retired colonel in the Army Reserve and a graduate of the College of William and Mary. He says the Brachman study "suffers from design flaws, incomplete reporting and relatively weak statistics." A panel of federal scientists who examined the study in 1969, when the vaccine originally was licensed, had similar criticisms.

Brachman also studied an earlier version of the vaccine than the one that's been used since the early 1990s. Government reports show that the potency of the vaccine was increased several times in the interim, leading some people to question how his research applies to the vaccine used today.

Pentagon officials and the FDA say these changes only improve the safety and reliability of the vaccine. But no studies using the normal criteria for vaccine approval have been conducted to demonstrate these statements.

The Cochrane Collaboration

The Pentagon says Cochrane is "an internationally respected group of scientists" devoted to evidence-based medicine. The organization sponsored one of the significant independent studies supporting the safety and effectiveness of the vaccine, according to the Penagon's anthrax vaccine Web site and other Pentagon documents.

The Cochrane Collaboration is a widely respected international group of scientists and doctors who evaluated the anthrax vaccine. But its report emphasized that there was no credible evidence it would work against inhaled anthrax, the type that troops would most likely encounter. It also found the evidence of safety questionable regarding the vaccine now used.

Tom Jefferson is a doctor and epidemiologist who co-authored the report and coordinates The Cochrane Collaboration's vaccine work. He says the military's reporting of his organization's findings regarding the vaccine is simply dishonest. "It's a misquote of scientific evidence for political means," he says. "If the evidence is so clear-cut, why do they have to misquote our study?"

Jefferson, an internationally recognized vaccine expert, says the only valid safety studies for the anthrax vaccine in the United States were for a different formulation from the one given to troops in recent years. His group studied the version, made in the 1950s, that was used in the Brachman study.

The current manufacturer and the military don't disclose exactly how the vaccine is different, he says, so it's hard to know whether the change is significant. What little is disclosed says the newer versions are more "potent" and "consistent."

As a result, no one outside the military and manufacturer can be sure that the vaccine now being given has ever been properly safety-tested, he says. "They should be testing vaccines before they give them to troops, not afterward," says Jefferson, who spent 18 years as a physician in the British army. "I don't like liberties taken with troops' lives."

Last year, Jefferson wrote a public criticism of the mandatory anthrax-vaccination program in the British Medical Journal. He says the Pentagon's statements for the vaccine were "political window-dressing."

Unless the anthrax program remains voluntary, he says, "It would appear that U.S. military personnel are being used as involuntary guinea pigs."

I've heard there was an experiment involving the anthrax vaccine that used people from the Persian Gulf War and later as guinea pigs. Is that true?

A lawsuit making its way up the ladder of federal courts maintains that because the anthrax vaccine was never properly approved for use by the FDA in the 1980s, it hasn't been deemed safe for general use and therefore is experimental.

The main argument for the "guinea pig" label seems to be the presence of squalene in some vials of the vaccine. Squalene is an oil and a vaccine additive, a component known as an "adjuvant" that helps the body more readily accept parts of a vaccine designed to fight disease. Squalene has never been approved for use in the United States. Despite evidence that some laboratory animals get very sick from squalene adjuvants, some versions of flu vaccine licensed overseas have been using it for years.

So what's the evidence for squalene as an experiment on military personnel?

First, several lots of the vaccine tested by independent laboratories and the FDA were found to contain squalene. This occurred after researchers at Tulane University and hospitals said they identified more than 100 patients with classic symptoms or diseases caused by autoimmune disorders. All had received anthrax vaccine from the "squalene" lots. A "lot" of vaccine is enough for about 200,000 doses.

The medical researchers who've linked squalene contamination with illness say efforts to pursue this work have been thwarted by the military and federal government, which will not finance it or supply needed data.

Felix M. Grieder is a retired Air Force colonel who commanded a squadron of aircraft at Dover, Del. He thinks that his troops were used in a squalene experiment involving anthrax vaccines in 1999.

Records kept by a base nurse show an unusually high rate of serious reactions. One pilot went into convulsions after the shot, and others were unable to fly for weeks and months, Greider says. The reactions were so severe, he called a halt to the shots for six days.

The shots resumed, but people kept getting sick. Grieder admits that he has no proof, other than the circumstantial evidence of higher-than-normal illnesses and confirmation that the lots of vaccine used on the base contained squalene.

Federal government analysis showed that efforts to improve the vaccine led to increased potency in some vials used at Dover, relative to other vials of the drug. The difference shouldn't have been significant, they say. FDA officials told Congress that the low levels of squalene found in the vaccine shouldn't be enough to affect anyone's health. But under questioning, they admitted that there was no data to support that theory.

The military, the FDA and the vaccine manufacturer say they don't know how the squalene got into the drugs.

Military researchers have been using squalene in experimental vaccine formulations since the 1940s, sometimes with disastrous results for participants. The military even patented a version of the anthrax vaccine with squalene. But it says the version has never been injected in anyone without his or her consent and knowledge that the use was experimental.

The GAO, the investigative arm of Congress, looked into the squalene accusations. It says there was a "pattern of deception" about the matter by the Pentagon - but no conclusive evidence of spiking the vaccine as an illegal test of the substance's effects.

It did point out that interviews with unnamed Pentagon officials revealed that military officials considered - but rejected - giving anthrax vaccinations with squalene to troops before the 1991 Persian Gulf War.

How can I determine whether my anthrax vaccination came from a lot with squalene?

Vaccines are made and packaged in bunches, known as lots. Shot records are supposed to include the lot number of the vaccine that you've been given. FDA-sponsored tests found squalene in lots FAV 008, FAV 020, FAV 030, FAV 038, FAV 043 and FAV 047. Not all lots were tested, however.

Pam Asa and other researchers at Tulane University in New Orleans say they've found evidence that other lots of the vaccine contained squalene. Their findings are disputed among scientists. The Tulane researchers say their research indicates that lots FAV 041, FAV 070 and FAV 071 contained squalene.

They also say that lots FAV 017, FAV 048b, FAV 066, FAV 068, FAV 069, FAV 073, FAV 074, FAV 075 and FAV 078 have been associated with autoimmune diseases or symptoms in troops who received these lots of vaccine.

Would the government really experiment on our troops?

Pentagon officials adamantly deny this was done with the anthrax vaccine. But in 1996, it acknowledged giving pyridostigmine bromide - then labeled an "investigational drug" by federal drug regulators - to troops without their consent in the 1991 Persian Gulf War.

The drug was designed to counteract possible nerve agents that the military thought the Iraqi army might have. "Investigational drug" is the government's label for a drug that hasn't been cleared for general use by the public. It usually means that the drug can't be given without informed consent, but the military got permission to give out the drugs without advising troops about its status. The law was changed to make the president the only official capable of giving this permission.

Previously, military personnel and some civilians - most notably blacks, American Indians and residents of sparsely populated Western states - were used in secret experiments involving radiation and biological warfare. The Government Accountability Office says the practice was so widespread - but so secretive - that it's difficult to count all the experiments. At least 230,000 military members have been part of radiological or biological weapon experiments from the 1940s through 1974, when a series of bacteriological warfare experiments was halted, the GAO says.

More recently, documents show that researchers and government officials knew about many of the health risks from Agent Orange, a plant-killing chemical used in the Vietnam War, in the 1960s and 1970s. Those risks weren't fully acknowledged until the mid-1990s. That's when veterans were finally guaranteed health care and compensation for serious physical and mental disabilities linked to the chemical's use.

I've heard that the military has been caught in a bunch of lies about the shot. Is that true?

"Lie" is a strong word. There are a few incidents where public statements by military officials have at least been found to be in error or are highly disputable.

For several years, the military's literature and Web site about the safety of the anthrax vaccine said it had been routinely used for three decades by thousands of veterinarians and people who worked with animal hides. Some of those references to veterinarians have been removed as critics of the shot found that very few veterinarians ever used it.

When government researchers analyzed use of the vaccine in the 1970s and 1980s, they concluded that the military was the primary customer of the vaccine, mostly in laboratories to protect workers creating weapons. At that time, it wasn't regularly given to troops.

In 1999, Air Force Maj. Gen. Paul A. Weaver - then the Air National Guard's director - testified to a congressional subcommittee that there had only been one person who'd refused to take the anthrax shot.

At the time, five Air Guard members who'd refused were sitting in the hearing room - and 37 refusals had been reported to the Pentagon. Dozens of others had been cited in news media reports.

An ethics complaint was filed with the Defense Department's inspector general. The official concluded that Weaver was defining "refusal" according to a definition that had been discussed by military leaders - but wasn't the same as "refusal" "in standard dictionary parlance."

The report concluded that Weaver's testimony wasn't as straightforward as the military's code of conduct for officers required but "was not willfully false or misleading."

The brochure now used to tell military members about the anthrax vaccination says that "U.S. anthrax vaccine has been FDA-licensed to prevent anthrax since 1970." On another page, it mentions that a U.S. District Court ruling requires the military to give it only to those who volunteer.

But it doesn't point out that the same court ruled the process that the government used in the licensing was flawed - thus making the drug's license invalid with respect to preventing illness from inhaled anthrax.

The U.S. Court of Appeals is scheduled to hear this case Dec. 1, and a ruling is expected in February.

In 1999 and 2000, the Pentagon and the FDA denied that there was any squalene in the anthrax vaccine given to military members. As noted earlier, squalene is an oil used to enhance the effectiveness of vaccines and is licensed for use overseas. It's never been approved for use in the United States. It's also been shown to cause autoimmune disorders in laboratory animals.

Laboratory research by critics of the shots led to discovery of squalene in several lots of the vaccine that had been given to troops. Those troops included members of Air Force and Air National Guard units in Delaware, which reported more than 30 people with long-term health problems after vaccination.

The military and the FDA finally acknowledged that "trace amounts" of squalene had been found in the vaccine - but denied that it had been put into the drugs on purpose. They couldn't say for sure, however, how the substance got into the vaccine or whether it might account for some problems suffered by military members who took it, including autoimmune reactions.

Government statements on squalene in the vaccine say it was probably "naturally occurring" and the result of oils from the hands of researchers. Squalene is part of the body's natural and necessary formulation of cholesterol and hormones, but its exact effect on the body is unknown.

Is this the best evidence that opponents of the vaccine have?

"Best" is in the eye of the beholder. Several studies involving veterans of the 1991 Persian Gulf War found a correlation between receiving the vaccine and higher-than-expected health problems in subsequent years. This research helped establish the legal legitimacy of Veterans Affairs Department claims by these men and women, establishing they had legitimate service-related disabilities that military doctors and others had been unable to diagnose.

But many of those veterans can't document receipt of the shot, in part because the shot wasn't routinely or accurately logged in their records in the weeks and months before the war. Pentagon officials attribute that to haste and security concerns, but the problem has continued to the present day, several government studies have found.

Another problem is that veterans in the studies linking the anthrax vaccination to health problems often couldn't say for sure whether the shots they'd received were for anthrax or other biological warfare agents.

Pentagon officials have discounted these studies. They've done so in large part because the studies also rely on subjective assessments of how veterans "feel" years after their service, as well as on memories of whether they were vaccinated for anthrax or other infections.

More Gulf War veterans reported feeling symptoms of fatigue, joint pain, memory loss and other symptoms typical of Gulf War illnesses, compared with veterans who didn't deploy to that war. But other studies have found that there's no connection between shots and ill health.

A two-year study of all causes of Gulf War veterans' illnesses - by an expert advisory panel for Veterans Affairs - concluded last year that there was enough evidence linking the anthrax vaccine to veterans' health problems to warrant an in-depth, long-term study to settle the issue further. The panel reviewed the evidence in April and decided that more work was needed.

There are also the hundreds of veterans who've made their health problems public in the past 15 years - in testimony to Congress, interviews with the news media, and submissions to federal agencies and the courts.

Volunteers who work with military personnel and veterans who think that their health problems relate to the anthrax shot say they've seen no drop-off in the number of people affected, despite the military's statements that the shots are safe.

Medical experts say it's often very difficult to assemble the scientific evidence to link a health problem with a vaccine unless a pattern has developed involving a number of similar cases. In the case of the anthrax shot, serious examination of possible patterns hasn't been done for even a decade. That means people who think that they're affected by the vaccine can usually say only that they got sick after getting the vaccine. It's not unusual for bona fide reactions to be delayed weeks or even months, so separating valid complaints from the invalid is difficult.

That's one reason that full and accurate reporting to the VAERS database is so important to researchers. The reports accumulate into a database where patterns can be seen and explored.

Can you get anthrax from the shot, like you could get polio from the polio vaccine?

That's never happened. Unlike some "live-virus" vaccines, the anthrax vaccine licensed in the United States contains only parts of cells from various types of anthrax. It's so incomplete, biologists say, it can't cause the disease.

I've heard that the problem might be the adjuvant or the preservatives, not the vaccine itself. Is that right?

A number of researchers have hypothesized that, but the theory remains unproven. The U.S. anthrax vaccine is often referred to as "AVA," for "anthrax vaccine absorbed." It's absorbed into an adjuvant known as aluminum hydroxide, a salt of aluminum used in many vaccines since the 1930s.

Adjuvants are used in many vaccines. They interact with the body to hold the antigen (the part of the vaccine that contains the effective agent) at the immunization point and release it over time, increasing the antibodies produced by the body. Antibodies are what form a body's defense to disease - or, in this case, exposure to anthrax.

In 2003, a French researcher published a report saying aluminum adjuvants caused chronic-fatigue syndrome in high numbers of patients. But his work hasn't been repeated by others and has been criticized. Aluminum adjuvants have been used since the 1920s and are now the only ones licensed in the United States.

Arezoo Campbell - a researcher at the University of California, Irvine - has published a number of studies involving the effect of aluminum on the body. She says she can document reactions in the brain to large exposures. But, she says, the possible effect of smaller doses - even accumulated over time with many vaccinations - isn't well known and needs to be researched more thoroughly.

How many members of the military have refused to take the shot? Pentagon officials say they aren't keeping an exact count. But they also say their informal surveys estimate that a little more than half of military members decided to accept the vaccine since the voluntary immunization program began May 3. The British military has been using a voluntary program for years and says about half its members get the shot.

As for military members who refused when the shot was mandatory, no one knows for sure. During the past five years, the Pentagon says, it can document 147 separations from the military based on refusal to accept the shot. But that doesn't include everyone who's refused but not been court-martialed or otherwise documented as refusing.

A report on the anthrax vaccination by a retired Army surgeon general says about 300 military men and women refused the shot between 1998 and 2002.

I've heard that the vaccine manufacturer has had problems. Is that true?

After the 1991 Persian Gulf War, it was determined that the FDA hadn't regularly inspected the only manufacturing site of the vaccine, in Michigan. Some people at the FDA said the Pentagon was responsible for monitoring the site.

In the late 1990s, the FDA learned that the process for making the vaccine had been changed without permission. It also learned that there were many problems with the manufacturing plant, owned and operated by the state of Michigan.

The plant was closed for renovations in 1998, then sold a few months later to a group of private investors, who formed BioPort Corp. The FDA forbid the use of any new vaccine for nearly four years while the problems were fixed. Such actions are extremely rare in the drug industry.

A GAO investigator told Congress during all this that there was evidence of alterations in the vaccine's potency. The official said the evidence indicated that there was 100 times more protective antigen (the vaccine's primary ingredient) in some lots of the vaccine, compared with the level used to obtain the original license.

Federal regulators and officials from BioPort, the vaccine's sole manufacturer, say all problems have been resolved. The license wasn't restored until January 2002, but the FDA approved the use of vaccine made at the plant before then - if it passed normal testing requirements.